title: Protective effects of cyclo(L-Leu-L-Tyr) against postischemic myocardial dysfunction in guinea-pig hearts.
abstract: The protective effects of cyclic dipeptides in alcoholic beverages were investigated in the perfused guinea-pig hearts subjected to ischemia and reperfusion. Subsequently, in order to determine the importance of cyclic dipeptide structure, the effects of cyclo(L-Leu-L-Tyr) (cLY) were compared with those of the newly synthesized non-cyclic dipeptides, L-Leu-L-Tyr (LY) and L-Tyr-L-Leu (YL). After reperfusion, pressure recovery (%) in the left ventricle reached a peak of over 90% in the presence of cLY (10(-6) M and 10(-5) M) (control: 22.9%). The recovery by LY and YL was significantly lower than that by cLY, and ATP levels simultaneously monitored using (31)P-NMR were already lower during the ischemic end period than those observed with cLY treatment. In perfused mitochondrial preparations, cLY significantly inhibited mitochondrial Ca(2+) ([Ca(2+)](m)) elevation in a similar way to that of the mitochondrial permeability transition pore (MPTP) inhibitor cyclosporin A. In vitro electron paramagnetic resonance (EPR) revealed that the active oxygen radicals quenching activity of cLY was greater than those of non-cyclic dipeptides. cLY inhibited caspase-3-induced apoptosis. The cyclic dipeptide structure inhibits opening of the MPTP by preventing [Ca(2+)](m) overload-induced apoptosis related to mitochondrial active oxygen radical accumulation in ischemia-reperfusion hearts.
authors.affiliation: College of Pharmacy, Kinjo Gakuin University, Moriyama, Nagoya 463–8521, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Mitsui-Saitoh
authors.forename: Tadashi
authors.initials: T
authors.lastname: Furukawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Akutagawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Hasada
authors.forename: Hideki
authors.initials: H
authors.lastname: Mizutani
authors.forename: Yumi
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Yamada
authors.forename: Masatake
authors.initials: M
authors.lastname: Niwa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hotta
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takaya
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002317:Cardiovascular Agents; D004151:Dipeptides; D033681:Mitochondrial Membrane Transport Proteins; D010456:Peptides, Cyclic; C562328:cyclo(leucyl-tyrosyl); D016572:Cyclosporine; D000255:Adenosine Triphosphate; D053148:Caspase 3; D002118:Calcium